Oxyethylation of imidazole compounds



United States Patent 3,178,446 OXYETHYLATION 0F IMIDAZOLE COMPOUNDS Remo Sannicolo, Milan, Italy, assignor to Institute Luso- Falmaco S.A.R.L., Lisbon, Portugal No Drawing. Filed Sept. 19, 1961, Ser. No. 139,064 Claims priority, applicgtsiosn Portugal, July 27, 1961,

7 Claims. (Cl. 260-609) where R represents a hydrogen atom, a halogen atom, an alkylie or arylic group, or a nitro group.

Ethylene carbonate, according to the method of invention, may be used not only in stoichiometric quantities, but also as a solvent and, therefore, may be added in excess. The oxyethylation may be carried out in the absence of catalysts or in the presence of slightly alkaline or acid catalysts. The rate of reaction is influenced by the extent that catalysts are used or not. Also, by changing the nature of the catalyst to acid or alkaline, different isomers can be obtained.

The reaction between ethylene carbonate and imidazole derivates may be carried out at temperatures ranging from 80 to 160 C., preferably from 100 to 145 C., a more or less gradual increase being allowable during the reaction.

The isolation of the desired product from the mixed reagents can be obtained through known methods, e.g., by extracting, after acidification, the excess ethylene carbonate with an adequate water-immiscible solvent, and then isolating the oxyethyl-imidazole compound after alkalinization of the solution.

The following examples are given to illustrate the method of invention and they are not meant to limit the invention:

Example 1 In a flask provided with a stirrer, internal thermometer and reflux, the following ingredients were introduced:

Grams Imidazole (M.P. 90-91 C.) 10 Ethylene carbonate 20 The mixture was then heated to 100 C., for two hours and allowed to cool. cc. concentrated hydrochloric acid were added. The solution was next extracted with chloroform to separate the ethylene carbonate which had not reacted. The acid water solution was then alkalized with potassium carbonate and extracted again with chlo- Example 2 The following ingredients were made to react to C., for two hours in the same manner as in Example 1:

Grams Z-methylirnidazole (M.P. 137140 C.) l0 Ethylene carbonate 20 After having processed the reaction product as described above, 5 gm. of 1-(2-oxyethyl)-2-methyl-imidazole were obtained through vacuum distillation. The product had a RP. of 130-l33 C. at (MS/0.25 mm., and the yield was 39% of the estimated theoretical value.

Example 3 The following ingredients were reacted at C., for 4 hours in an apparatus as set forth in Example 1:

Grams 5 -nitro-2-methylimidazole 10 Ethylene carbonate 50 They were then brought to 145 C. for another 3 hours. After the reacting mass was treated with chloroform in acid medium and the pH adjusted to 7, a small quantity of l-(Q-oxyethyl)-5-nitro-2-methylimidazole with M.P. 156-157 C. and 2 gm. of l-(2-oxyethyl)-4-nitro-2- methyl-imidazole, with M.P. 140 C. were obtained.

Example 4 In the same manner as in Example 1, the following ingredients were reacted:

Grams S-nitrO-Z-methylimidazole l0 Ethylene carbonate 20 p-Toluenosulphonic acid 5 The reaction was carried out under agitation at C., for 15 hours. After cooling, water was added to the reacting mass which was then acidified with concentrated hydrochloric acid and extracted with chloroform to recover the ethylene carbonate which was not reacted. The acid solution was then alkalized with 30% sodium hydroxide, and extracted again with chloroform. This second chloroform extract was evaporated to dryness and the residue was recrystallized from isopropanol. The residue 'had .a M.P. of 156-157 C. 4.2 gms. of 5-nitro-2- methyl-imidazole, with M.P. 241-242 C. was recovered, through neutralization, from the acid mother-Waters.

Example 5 The same procedure and amounts set forth in Example 3 were used to react the sodium salt of irnidazole (obtained through reaction of the imidazole with sodium alcoholate), with ethylene carbonate. A product is obtained which consisted solely of 1-(2-oxyethy1)-4-nitro- Z-methyl-imidazole, which had an M.P. of C.

What is claimed is:

l. A method for the preparation of oxyethyl-imidazole compounds of the formula in which R stands for one of the group consisting of a hydrogen atom, a halogen atom, an alkylic, arylic residue,

and a nitro group, comprising reacting imidazole derivatives of the formula wherein R has the aforementioned values, with ethylene carbonate.

2. A method according to claim 1, wherein the reaction is carried out in the absence of catalysts.

3. A method according to claim 1, wherein the reaction is carried out in the presence of slightly alkaline catalysts.

4. A method according to claim 1, wherein the reaction is carried out in the presence of slightly acid catalysts.

5. A method according to claim 1, in which ethylene carbonate is used in excess of the stoichiometric quantities, and acts as a solvent.

6. A method according to claim 1, wherein the re- References Cited by the Examiner UNITED STATES PATENTS 9/48 Carlson 260-573 7/60 Jacob et al. 260573 OTHER REFERENCES Elderfield: Heterocyclic Compounds, vol. 5, p. 205 (1957 Carlson et a1.: 3'. Am. Chem. Soc., vol. 69, p. 1952-6 (1947).

IRVING MARCUS, Primary Examiner.

DUVAL T. MCCUTCHEN, WALTER A. MODANCE,

Examiners. 

1. A METHOD FOR THE PREPARATION OF OXYETHYL-IMIDAZOLE COMPOUNDS OF THE FORMULA 